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From: TSS ()
##################### Bovine Spongiform Encephalopathy ##################### Prion Toxicity: All Sail and No Anchor Adriano Aguzzi Within the past 2 years, our understanding of the infectious particles responsible for fatal neurological conditions such as mad cow disease, scrapie, and Creutzfeld-Jakob disease has seen considerable progress (1). There is now strong evidence that prions, the culprit infectious particles, can be synthesized in systems that are completely free of cellular material (2, 3). This may essentially settle the score as to the purely proteinaceous nature of the infectious agent. As to the march of prions toward the brain, or "neuroinvasion," a wealth of players has been uncovered, as well as an intricate relationship between immunological and nervous compartments of the host organism (4, 5). Still, the physiological function of PrPC, the form of prion protein that cells normally harbor, remains essentially mysterious. Also, we do not understand how the infectious form of the prion protein, a structurally distorted form of its normal counterpart, achieves brain damage. A tantalizing inroad has now been made by Chesebro and colleagues as to the latter question on page 1435 of this issue (6). The causative agent of transmissible spongiform encephalopathies (TSEs) such as scrapie is PrPSc, a misfolded, proteaseresistant version of the normal PrPC protein (encoded by the Prnp locus in mice). PrPSc forms orderly aggregates that often progress into large extracellular deposits commonly described as brain plaques. It is argued that PrPSc multiplies by recruiting and converting PrPC into further PrPSc. But this hypothesis does not explain how infectious prions proceed to induce the spongy brain lesions of TSEs and, eventually, extensive neuronal death. Curiously, PrPSc itself is innocuous: When the brain of a mouse lacking normal prion protein is grafted with brain tissue replete with PrPC and then subsequently exposed to infectious prions, sizable amounts of PrPSc are produced, yet the mouse fails to develop TSE (7). So why aren't PrPC-deficient neurons affected by the infectious agent? Chesebro et al. have investigated this question in a sophisticated model system. During its early biogenesis, PrPC is directed to the lumen of the endoplasmic reticulum, thus entering the cellular secretory pathway. A glycosylphosphatidylinositol (GPI) lipid anchor is then added to its C terminus, tethering the protein to the outer side of the cell membrane. Chesebro et al. redacted a Prnp transgene to remove the signal peptide responsible for GPI anchoring. As a consequence, the resulting GPI-negative transgenic mice expressed a monomeric, soluble secreted form of PrPC. When infected with PrPSc, the GPI-negative transgenic mice never developed clinical prion disease. Quite surprisingly, though, their brains were packed with PrPSc plaques! Evidently, removal of the GPI anchor abolished susceptibility to clinical disease while preserving the competence of the soluble PrPC molecule to support prion replication. This interpretation fits very nicely with the growing body of evidence that normal prion protein may function as a signaling molecule, just like many other GPI-linked proteins. Altered PrPC signaling may therefore be unhealthy (see the figure). Indeed, cross-linking of PrPC on the surface of hippocampal neu- rons with antibodies sends the cells into untimely demise (8). Hence, we are led to wonder whether the damage wrought on neurons by clustered PrPC proteins relates to TSE neurodegeneration. If so, could the mechanism by which prion infections lead to brain damage be related to the normal function of PrPC? Mice lacking normal prion protein live a healthy and long life without pathological phenotypes, so loss of function of PrPC is most certainly not a cause of brain damage in TSE. Could any gain of function of PrPC trigger disease pathogenesis? Morphological findings would appear to depose against this hypothesis as well. Although the clustering of molecules at the cell surface is a common way to initiate signaling, injecting antibodies to PrPC into a mouse brain does not elicit spongiosis. Conversely, ordered aggregation is a crucial event in the formation of PrPSc and may represent the true mechanism by which infectivity is generated (9). Chesebro et al.'s findings yield powerful support for a link between the cell surface topology of PrPSc and prion disease pathogenesis. By disengaging PrPC from the cell surface, the authors have effectively uncoupled clinical disease from prion replication, PrPSc formation, and its assembly into higher order aggregates and the hallmark brain plaques. It is almost unavoidable to conclude that prion replication avails itself of membrane-bound signal transducers to elicit brain damage. Another twist to Chesebro et al.'s story relates to the structural requirements for prion replication. In contrast to GPI-negative mice, transgenic mice that express a soluble dimeric version of PrPC do not accumulate PrPSc in their brains or spleens upon prion infection, nor do they develop or transmit TSE (10). Instead, the soluble dimeric form efficaciously competes with endogenous PrPC and delays prion pathogenesis in normal mice. In combination with Chesebro et al.'s results, this indicates that detachment of PrPC from the membrane does not necessarily abolish its prion replication competence. The soluble dimeric form may act as a dominant-negative form that sequesters PrPSc, rendering it unavailable and thereby inhibiting disease progression. Brain extracts of prion-infected GPInegative mice did not elicit plaque formation when injected into other GPI-negative mice. The importance of this failed attempt at transmission is unclear, but such a result may point to some kind of def iciency in the prion replication machinery of these transgenic mice. For all the insight brought about by Chesebro et al.'s findings, a central question remains. Accruing evidence suggests that signaling at the membrane involving PrPC underlies TSE pathogenesis. Infectious prions may damage the brain by distorting signaling events that PrPC normally controls. If that is true, the best way to find out what exactly goes wrong in the brains of prion-infected individuals may be to sort out the normal function of PrPC. Yet despite 13 years of availability of mice lacking normal prion protein, progress toward resolving the latter question has been painstakingly slow. Although Chesebro et al.'s work exemplifies the awesome power of mouse transgenetics, a next important step may consist of porting the prion signaling system to simpler, genetically tractable organisms such as worms, flies, or fish, whose use is already having a tremendous impact on the study of other neurodegenerative diseases. References 1. A. Aguzzi, C. Haass, Science302, 814 (2003). 2. J. Castilla, P. Saa, C.Hetz, C. Soto, Cell121, 195 (2005). 3. G. Legname et al., Science305, 673 (2004). 4. M. Prinz et al., Nature425, 957 (2003). 5. M. Heikenwalder et al., Science307, 1107 (2005); published online 20 January 2005 (10.1126/ science.1106460). 6. B. Chesebro et al., Science308, 1435 (2005). 7. S. Brandner et al., Nature379, 339 (1996). 8. L. Solforosi et al., Science303, 1514 (2004); published online 29 January 2004 (10.1126/science.1094273). 9. J.T. Jarrett, P.T. Lansbury Jr., Cell73, 1055 (1993). 10. P. Meier et al., Cell113, 49 (2003). 10.1126/science.1114168 P E R S P E C T I V E S CELL BIOLOGY Prion Toxicity: All Sail and No Anchor Adriano Aguzzi The author is at the Institute of Neuropathology, University Hospital of Zürich, CH-8091 Zürich, Switzerland. E-mail: adriano@pathol.unizh.ch =========================== TSS #################### https://lists.aegee.org/bse-l.html ####################
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